The Ubiquitin Proteasome System as a Therapeutic Area in Parkinson’s Disease

The Ubiquitin Proteasome System as a Therapeutic Area in Parkinson’s Disease

Progenra Inc, February 2023

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. There are no available therapeutics that slow or halt the progressive loss of dopamine-producing neurons, which underlies the primary clinical symptoms. Currently approved PD drugs can provide symptomatic relief by increasing brain dopamine content or activity; however, the alleviation is temporary, and the effectiveness diminishes with the inevitable progression of neurodegeneration.

Discovery and development of disease-modifying neuroprotective therapies has been hampered by insufficient understanding of the root cause of PD-related neurodegeneration. The etiology of PD is complex and involves a combination of genetic and environmental factors.

Although a single cause has yet to emerge, genetic, cell biological and neuropathological evidence implicates protein aggregation and mitochondrial dysfunction. Postmortem PD brains show pathognomonic Lewy body intraneuronal inclusions composed of aggregated α-synuclein, indicative of failure to degrade misfolded protein. Mutations in the genes that code for α-synuclein, the E3 ubiquitin ligase Parkin and the mitochondrial kinase PINK1, cause rare inherited forms of PD. While many ubiquitin ligases label proteins with ubiquitin chains to mark proteins for degradation by the proteasome, Parkin has been shown to mark dysfunctional mitochondria for degradation by mitophagy.

The ubiquitin proteasome system participates in several aspects of the cell’s response to mitochondrial damage, affording numerous therapeutic opportunities to augment mitophagy and potentially stop PD progression. Progenra’s scientists recently published a review that examined the role and therapeutic potential of such UPS modulators, exemplified by both ubiquitinating and deubiquitinating enzymes.